This invention relates to an article of manufacture comprising a stabilized aqueous solution of pure 5-aminosalicylic acid (5-ASA).
5-ASA is a position isomer of the well known anti-tubercular agent p-aminosalicylic acid (4-ASA). However, it has completely different chemical and therapeutic properties. One of the most difficult chemical problems of 5-ASA is its lack of stability in aqueous solutions or suspensions.
Since it has been discovered to be the active moiety of sulfasalazine (used to treat ulcerative colitis), 5-ASA has been the focal point of numerous clinical investigations. Dosage forms for these investigations included powders for reconstitution, short-lived suspensions (7-14 days), wax suppositories and oral tablets. Investigators have recognized that 5-ASA is highly degradable in aqueous systems.
Aqueous solutions of 5-ASA are so unstable that heretofore they have been effectively eliminated as a commercially viable form for rectal administration. Attempts to protect them from decomposition upon prolonged storage, e.g., by storing them in sealed glass containers or under refrigeration have proved futile. Non-aqueous rectal forms of 5-ASA were not a viable alternative because of concerns that they might be less effective than aqueous forms and 5-ASA is substantially ineffective orally to treat diseases of the colon, such as ulcerative colitis. Therefore, the prior art approach to the problem has been to develop a pro-drug which will form 5-ASA in situ in the colon.
In its sulfasalazine pro-drug form, 5-ASA is chemically stabilized by the azo group linking it to sulfapyridine. When sulfasalazine reaches the colon by either oral or rectal administration, the colonic bacteria reduce the azo linkage, freeing 5-ASA and sulfapyridine. Sulfapyridine has no therapeutic benefit towards ulcerative colitis but nevertheless is responsible for dose-related side-effects. Numerous other pro-drugs have been considered wherein 5-ASA is azo-linked to an innocuous substance or a second molecule of 5-ASA. This constitutes a method of promoting chemical stability but may result in some of the disadvantages associated with sulfasalazine. For example, azo forms of 5-ASA must reach the colon to be metabolized and bioavailability is questionable since metabolism may not be complete, especially in patients on antibiotics.
Some physicians have supplied 5-ASA to the patient in dry form, to be made up by the patient with an aqueous solution immediately prior to rectal administration, or in small batches as aqueous solutions which would be used up by the patient before significant color formation occured. Neither of these approaches were completely satisfactory from a physician-patient point of view.
We therefore investigated the possibility of producing an aqueous solution of 5-ASA which was stabilized against decomposition and color formation for the prolonged storage period required of a commercial pharmaceutical product. In doing so, it was found that unless the starting 5-ASA is very pure, it is virtually impossible to prevent its decomposition, apparently because of the auto-catalytic effects of the impurities on decomposition and color formation. Therefore, the first step in achieving a storage-stable 5-ASA was the development of an acceptable purification process, since the commercially available 5-ASA (in production lots) is a technical grade.
We found that pure 5-ASA suitable for use in the compositions of this invention can be produced by decolorizing an acidic concentrated solution thereof with activated charcoal. In contradistinction, its position isomer, 4-ASA, is purified via its sodium salt. See, e.g., U.S. Pat. No. 2,658,073 and 2,844,625. However, 5-ASA is unstable in alkaline solutions and its purification via its sodium salt is therefore not feasible.
The next step in our investigation was finding a way to prevent the decomposition of and color formation in initially colorless solutions of substantially pure 5-ASA. In doing so, we found that bisulfite would inhibit decomposition of and initial color formation in such solutions. This was surprising because even solutions of 5-ASA which had been carefully purged with nitrogen developed color upon long term storage, after packaging using conventional pharmaceutical equipment. Therefore, an anti-oxidant seemed inappropriate as a stabilizing agent.
Sulfite has been used in the prior art as stabilizers or antioxidants for a wide variety of drugs representing broad chemical and pharmacological classes. See Louis C. Schroeter, "Sulfur Dioxide. Applications in Foods, Beverages and Pharmaceuticals", pp. 228-265, esp. 257-261 and cases cited therein (Pergamon Press, 1966).
U.S. Pat. No. 2,647,843 incorrectly teaches that aqueous solutions of 4-ASA are stabilized against color formation resulting from oxidation upon storage with sulfites or bisulfites. In fact, 4-ASA is decomposed by decarboxylation at acid pH, not by oxidation as is 5-ASA. Early researchers believed that because bisulfite prevented color formation, it stabilized 4-ASA solutions. This later was proved to be incorrect. Actually, only the formation of the azoxy-benzene chromagen was inhibited (Pharm. Sci., 60, No. 12, Dec. 1977, pp. 1886-7). It is alkaline pHs, not bisulfite, which prevents decomposition of the 4-ASA.
Because bisulfite alone did not prevent color formation in the 5-ASA solutions upon prolonged storage, we investigated the use of a combination of bisulfite and the chelating agent ethylenediaminetetraacetic acid, in the event the delayed color formation was due to the presence in the solution of trace amounts of heavy metals which are known to catalyze color-forming reactions.
The use of the combination of sodium bisulfite (antioxidant) and the disodium salt of EDTA (chelating agent) to stabilize injectable solutions of chlorpromazine hydrochloride solution in disposable cartridges is claimed in U.S. Pat. No. 3,777,019. Color formation in such solutions was due to the oxygen intrusibility of the disposable cartridges in which the chlorpromazine solution was marketed, rather than the intrinsic instability of the chlorpromazine, which is storage stable in flame-sealed all-glass ampuls or rubber-closured glass vials. Martindale, The Extra Pharmacopedia, 28th Ed., pp. 1291-2 (The Pharmaceutical Press, London, 1982) states that sodium metabisulfite is widely used as an antioxidant at concentrations ranging from 0.01% to 1% in solutions (usually in acid preparations with sodium sulfite preferred for alkaline preparations), especially those that contain drugs which are readily oxidized to form highly colored products and that a chelating agent, such as sodium edetate, is sometimes added thereto to remove heavy metal ions which often catalyze auto-oxidation reactions.
The decomposition of solutions of 5-ASA appears not to be metal ion initiated, since EDTA alone is completed ineffectual in inhibiting that decomposition whereas the bisulfite alone ordinarily inhibits color formation, except upon prolonged storage. In contradistinction to 4-ASA, 5-ASA decomposes as a result of oxygen attack on the amino group, yielding 2,5-dihydroxybenzoic acid as a major decomposition product. The mechanism for color formation is not known. However, intense color formation can occur even with only slight decomposition of the 5-ASA precentage-wise.
We ultimately found that EDTA did not improve the long term protection against color formation in aqueous solutions of 5-ASA achieved with bisulfite alone. Instead, paradoxically the bisulfite itself, at least in amounts we initially employed, was responsible for the color formation upon long terms storage, even though it did prevent loss of assay and short term (within 30 days) color formation.
Contrary to popular belief, we found that the decomposition of and color formation therein upon short term storage in initially colorless acid aqueous solutions of substantially pure 5-ASA is not due to the reaction of the 5-ASA with the water. Instead, it is due to the trace amount of atmospheric oxygen which is present in the solution after conventional pharmaceutical processing and packaging, even after nitrogen purging of the free space of the container in which the 5-ASA is packaged. We found that extremely small amounts of oxygen are capable of triggering such decomposition (loss of 5-ASA assay strength) and color formation (which can occur even with only negligible loss of 5-ASA assay strength).
In parent application Ser. No. 536,428, there are disclosed examples of aqueous colorless solutions of pure 5-ASA which were protected with 0.468% w/w of potassium metabisulfite against color formation for several months when stored in a sealed polyethylene squeeze bottle adapted for rectal administration of the 5-ASA. This amount of bisulfite was required because the solutions were exposed to atmospheric oxygen during storage as a result of being stored in plastic bottles having a substantial oxygen transmission rate. However, it was discovered that the solutions nevertheless ultimately developed color upon prolonged storage. We found that the amount of bisulfite required to ensure protection of 5-ASA against color formation resulting from reaction with the atmospheric oxygen transmitted thereto through the walls of the plastic bottle upon prolonged storage itself ultimately imparted an undesirable color change in the solution. The reason for such color change is not known other than it is due solely to the bisulfite in such solutions.
It is an object of this invention to provide means for preventing the color formation which occurs in aqueous 5-ASA solutions upon both short term and long term storage.
It is another object to provide pharmaceutical articles of manufacture which incorporate such means.
Upon further study of the specification and appended claims, further objects and advantages of this invention will become apparent to those skilled in the art.